p53 mediates its function as a tumor suppressor through the transcriptional up-regulation of genes required for induction of cell cycle arrest or apoptosis (Vousden 2007, Nat Rev MCB; 8(4):275-83). It is estimated that about 50% of all tumors have lost, or carry an inactivating mutation in, p53 (Soussi 2001, Nature Rev Cancer; 1(3):233-240). In the remaining 50% of tumors, p53 is inactivated by various other means, including enhanced expression of its negative regulator, MDM2. MDM2 inhibitors can help restore the TP53 function.
The D-cyclin-CDK4/6-INK4a-pRb pathway is frequently disrupted in cancer to favor cell proliferation. Eighty percent of human neoplasms maintain functional pRb and instead increase CDK4/6 kinase activity to keep pRb inactivated via multiple aberrations. There are over 130,000 new cases of sarcoma worldwide each year, accounting for approximately 1% to 3% of all malignancies. Inhibitors of CDK4/6 are known that ameliorate effects of overactivated CDK4/6 kinase activity in tumors.
Liposarcoma (LPS) is a rare and heterogeneous disease that represents the most frequent soft tissue sarcoma in adults, accounting for approximately 12.8% of all sarcomas (Gadgeel 2009, Cancer; 115(12): 2744-2754). The annual incidence is estimated to be 2.5 per 1 million inhabitants in population-based studies (Kindblom 1975, Acta Pathol Microbiol Scand Suppl. (253):1-71). LPS is a malignant mesenchymal neoplasm that is composed of a varying proportion of mature adipocytic proliferation and a degree of cellular atypia. According to histology. LPS can be subdivided into five subtypes, i.e. well differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma, round cell liposarcoma, and pleomorphic liposarcoma, corresponding to three main biologic groups. Among these, the most common are the WDLPS (40-45% of all LPS) and DDLPS (5% of all LPS). WDLPS/DDLPS is considered as a biphasic disease, the dedifferentiated component being more aggressive and leading to metastasis. This component can either arise de novo or from the slowly growing well-differentiated component of the tumor.
In spite of numerous treatment options for patients with specific types of cancer, there remains a need for effective and safe combination therapies that can be administered for the effective long-term treatment of cancer.